生物
Wnt信号通路
癌症研究
细胞毒性T细胞
三阴性乳腺癌
肿瘤微环境
免疫系统
CD8型
乳腺癌
转移
癌症
免疫学
信号转导
细胞生物学
生物化学
体外
遗传学
作者
X. Wang,Mei Feng,Tengfei Xiao,Baosen Guo,Danyang Liu,Chenglong Liu,Jinpeng Pei,Qiaofeng Liu,Yi Xiao,Rina Rosin‐Arbesfeld,Ying Shi,Yang Zhou,Ming Yang,Yuxiong Feng,Yi‐Zhou Jiang,Zhimin Shao,Ker Yu,Di Zhu
出处
期刊:Oncogene
[Springer Nature]
日期:2021-03-25
卷期号:40 (16): 2982-2997
被引量:21
标识
DOI:10.1038/s41388-021-01756-y
摘要
Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to a lack of well-defined molecular targets. The Wnt/β-catenin pathway is known to be activated in many TNBC patients and BCL9 and BCL9L are important transcriptional co-activators of β-catenin, but whether inhibition of BCL9/BCL9L can suppress TNBC growth and the underlying mechanism are not fully understood. Here we demonstrate that the expression of BCL9 and BCL9L is directly correlated with malignancy in TNBC patient tumors and that BCL9 and BCL9L promote tumor cell growth, cell migration and metastasis in TNBC models. Mechanistically, we found that BCL9/BCL9L promotes tumorigenicity through both the Wnt and TGF-β pathways. Besides, BCL9/BCL9L expression inversely correlates with CD8+ T cell infiltration in TNBC and BCL9/BCL9L inhibits the infiltration of CD8+ T cells in the tumor microenvironment. hsBCL9CT-24, an inhibitor of BCL9/β-catenin peptides, promotes intratumoral infiltration of cytotoxic T cells, reducing regulatory T cells (Treg) and increasing dendritic cells (DCs). Inhibition of BCL9/BCL9L and TGF-β suppresses activity of Treg. TGF-β signaling increases tumor infiltration of cytotoxic CD8+ T cells. In accordance, genetic or pharmacological inhibition of BCL9/BCL9L synergizes with PD-1/L1 antibodies to inhibit tumor growth. In summary, these results suggest that targeting BCL9/BCL9L has a direct anti-tumor effect and also unleashes an anti-cancer immune response through inhibition of both Wnt and TGF-β signaling, suggesting a viable therapeutic approach for TNBC treatment.
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